Vaso-occlusion (VOC) and its clinical manifestation, pain, are the hallmark of sickle cell disease (SCO) and are the main causes of hospitalization and both short- and long-term disability in patients with SCD. Adhesion of red cells containing primarily hemoglobin S (SSRBCs) plays a major role in the vasoocclusive process, but no anti-adhesive therapy for SCO is yet available or even in clinical trial. We have discovered that sickle red blood cell (SSRBC) adhesion results from activation of RBC adhesion receptors via the [unreadable]2- adrenergic receptor, a response not seen in normal RBCs. Physiologic doses of epinephrine increase adhesion of SSRBCs, which then leads to stimulation of pro-adhesive molecules by endothelial cells. We have recently shown that propranolol inhibits epinephrine-induced SSRBC adhesion both in vitro and in an animal model and that a single dose of propranolol given to SCO patients can reduce RBC adhesion measured in vitro, without significant changes of blood pressure and heart rate from baseline. This discovery makes possible an entirely novel approach to SCO treatment-the use of an FDA-approved drug, propranolol, as the first anti-adhesive therapy for SCD. Here we are proposing to study the efficacy of chronic propranolol therapy in reducing sickle red blood cell adhesion to vascular endothelium. This will be a phase II open-label study to find out whether chronic propranolol therapy can safely reduce the adhesion of~ SSRBCs to the endothelium and thus improve in vivo SSRBC circulatory characteristics in the microvasculature. Forty patients will be studied. Subjects will be treated with a twice a day dose of 40 mg of propranolol for a total of 6 weeks during which their clinical data will be collected. In vitro and in vivo adhesion studies will be performed to evaluate the drug effect on SSRBC adhesion. Overall, a clinical and laboratory parameters will be used to measure the efficacy and safety of chronic propranolol therapy, in reducing SSRBC adhesion, with the long-term goal of gathering data supporting the development of a large scale, randomized, multicenter study to determine the efficacy of propranolol in reducing VOC in SCD. RELEVANCE (See instructions): Development of therapies to treat or prevent vaso-occlusion in sickle cell disease is paramount to reducing the disease's morbidity and mortality. Our preliminary data suggest that propranolol, an inexpensive and widely available drug, might be safe and useful for this purpose. Thus, we propose to test this hypothesis in a Phase II single center clinical study.